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Cancer Res. 2017 Jan 15;77(2):566-578. doi: 10.1158/0008-5472.CAN-16-1901. Epub 2016 Nov 21.

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.

Author information

1
Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut. vikram.wali@yale.edu christos.hatzis@yale.edu.
2
Yale Cancer Center, New Haven, Connecticut.
3
Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut.
4
Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut.

Abstract

Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem-like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566-78. ©2016 AACR.

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